Benign prostate hyperplasia (BPH) is a nonmalignant enlargement of the prostate gland. BPH is the most common non-malignant proliferative abnormality found in any internal organ and the major cause of morbidity in the adult male. The initial development of BPH begins as early as 30 to 40 years of age and the prevalence is approximately 10% for that age group. With advancing age, the prevalence of BPH increases progressively. BPH occurs in over 75% of men over 50 years of age, reaching 88% prevalence by the ninth decade. The general aging of the United States population, as well as increasing life expectancies, is anticipated to contribute to the continued growth in the number of BPH sufferers.
BPH frequently results in a gradual squeezing of the portion of the urethra which traverses the prostate (prostatic urethra). This causes patients to experience a frequent urge to urinate because of incomplete emptying of the bladder and a burning sensation or similar discomfort during urination. The obstruction of urinary flow can also lead to a general lack of control over urination, including difficulty initiating urination when desired, as well as difficulty of urinary retention because bladder outlet obstruction and a uncontrollable urinary continence due to residual urine, a condition known as overflow urinary incontinence.
There are two components of BPH. The first component is due to enlargement of the prostate gland, which may result in compression of the urethra and obstruction to the flow of urine from the bladder. The second component is due to increased smooth muscle tone of the bladder neck and the prostate itself, which interferes with emptying of the bladder and is regulated by α1 adrenergic receptors (α1-Ars).
The androgens testosterone and dihydrotestosterone (DHT) are contributing factors in producing BPH in the prostate. Testosterone is converted by 5-alpha-reductase (5α-reductase) to DHT, which is about five times more potent than testosterone due to its greater binding affinity to the androgen receptor. DHT binds to cytoplasmic receptors in the prostate, where it initiates RNA and DNA synthesis. This action, in turn, induces protein synthesis and abnormal growth of the prostate. There are two isoforms of 5-α reductase in mammals, particularly humans. The type 1 isoenzyme is highly expressed in liver and skin, has a lower affinity for testosterone, and behaves more like a catabolic reagent. In contrast, the type 2 isoenzyme is mainly expressed in androgen target tissues, has higher affinity for testosterone, and amplifies the androgenic effects of testosterone by converting it into DHT.
Androgen deprivation can decrease the obstructive symptoms of BPH. Moreover, current clinical evidence indicates that inhibition of 5α-reductase reverses the symptoms of BPH in human males (Strauch, G. et al., Eur. Urol., Vol. 26, pp. 247-252 (1994); Rhodes, L. et al., Prostate, Vol. 22, pp. 43-51 (1993)). Further, 5α-reductase activity appears to be higher in cells obtained from BPH tissue than from normal prostate tissue. (Bone, K., The European Journal of Herbal Medicine, Vol. 4(1), pp. 15-24 (1998)).
Knowledge of how 5α-reductase regulates prostate growth has resulted in the development of drugs, such as the 5α-reductase type 2 selective inhibitor finasteride, for use in controlling the symptoms of BPH and in preventing urinary retention. Finasteride (PROSCAR) blocks the conversion of testosterone to DHT and has been found to reduce the size of the prostate, leading to an increase in peak urinary flow rate and a reduction in symptoms (Strauch et al. 1994; Rhodes et al. 1993; Russel et al (1994), Annu. Rev. Biochem. 63: 25-61).
Patients diagnosed with BPH generally have several options for treatment, including watchful waiting, surgical intervention, laser assisted prostatectomy, thermal therapies, and drug therapy. Watchful waiting is often chosen by men who are not or minimally bothered by the symptoms of BPH, and it includes regular checkups and monitoring to see if the condition remains tolerable. Surgical intervention is the currently accepted treatment for BPH and is generally reserved for patients with intolerable symptoms or those with significant potential symptoms if treatment is withheld. Currently, of the patients suffering from BPH, only a very small fraction (2-3%) is being treated by surgery. Surgical therapy includes including transurethral resection of the prostate (TURP), transurethral incision of the prostate (TUIP), and open surgery. Surgical procedures, while effective in relieving the symptoms of BPH, result in substantial damage being inflicted upon the prostatic urethra. Laser assisted prostatectomy and heat ablation therapies, while less invasive, also cause substantial damage to the prostatic urethra. As well, surgical treatment of BPH is estimated to cost over a billion dollars per year, with the expectation that these costs will rise as the aged male population increases.
Drugs useful for the treatment of BPH are designed to treat prostate enlargement, which characterizes BPH, by shrinking the prostate or by inhibiting or slowing the growth of prostate cells. Finasteride (Proscar®, Merck) is one such therapy which is indicated for the treatment of symptomatic BPH. Finasteride is a competitive inhibitor of the enzyme 5α-reductase type 2, which is responsible for the conversion of testosterone to dihydrotestosterone in the prostate gland. Other drugs are designed to relax the muscles in the prostate and bladder neck to relieve urethral obstruction. Terazosin (Hytrin, Abbott) is an adrenergic receptor blocking agent (α 1-AR blockers) which acts by decreasing the smooth muscle tone within the prostate gland, urethro and bladder.
BPH, if left unabated, can have dire health consequences. BPH can lead to acute urinary retention (complete inability to urinate), serious life threatening urinary tract infections and urosepsis and permanent bladder and kidney damage. Innovative approaches are urgently needed at both the basic science and clinical levels to treat BPH. The development of new non-invasive therapeutic approaches could result in a substantial increase in the number of BPH patients who elect to receive therapy. The present invention is directed to satisfying this need.